Method for therapeutic treatment of rosacea

ABSTRACT

A regimen and a pharmaceutical composition for the treatment of rosacea are described. The regimen includes topically applying to the skin of a subject in need of such treatment a pharmaceutical composition comprising about 1% w/w to about 10% w/w benzoyl peroxide as an active ingredient, and the pharmaceutically acceptable carrier or excipient, where the benzoyl peroxide is the only active ingredient in the pharmaceutical composition, and the pharmaceutical composition is a cream or an emulsion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) from U.S.Provisional Application No. 62/977,974, filed Feb. 18, 2020, U.S.Provisional Application No. 62/977,952, filed Feb. 18, 2020, U.S.Provisional Application No. 62/972,896, filed Feb. 11, 2020, U.S.Provisional Application No. 62/972,310, filed Feb. 10, 2020, U.S.Provisional Application No. 62/960,384, filed Jan. 13, 2020, U.S.Provisional Application No. 62/925,258, filed Oct. 24, 2019, U.S.Provisional 62/871,286, filed Jul. 8, 2019, U.S. Provisional 62/871,283,filed Jul. 8, 2019, U.S. Provisional 62/807,356, filed Feb. 19, 2019,and U.S. Provisional 62/807,368, filed Feb. 19, 2019, the contents ofwhich are incorporated in their entirety as if fully set forth herein.

TECHNICAL FIELD

This application relates to methods and compositions for the therapeutictreatment of skin conditions and afflictions, such as rosacea, andsymptoms and considerations associated therewith, including topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition comprising benzoyl peroxide having high skinpermeation and penetration, preferably in the upper layers of the skin.

BACKGROUND

Rosacea is a chronic disease of inflammatory dermatitis that mainlyaffects the median part of the face and the eyelids of certain adults.It is characterized by telangiectatic erythema, dryness of the skin,papules and pustules. Conventionally, rosacea develops in adults fromthe ages of 30 to 50, and more frequently affects women, although thecondition is generally more severe in men. Rosacea is a primitivelyvascular condition whose inflammatory stage lacks the cysts andcomedones characteristic of common acne.

Factors that have been described as possibly contributing towards thedevelopment of rosacea include, for example: the presence of parasitessuch as the Demodex folliculorum; the presence of bacteria such asHelicobacter pylori (a bacterium associated with gastrointestinaldisorders); hormonal factors (such as endocrine factors); climatic andimmunological factors; and so forth.

Rosacea develops in four stages over several years, in spasms aggravatedby variations in temperature, alcohol, spices, exposure to sunlight andstress. The various stages of the disease are:

Stage 1 (stage of erythema episodes): the patients have erythrosisspasms due to the sudden dilation of the arterioles of the face, whichthen take on a congestive, red appearance. These spasms are caused byemotions, meals and temperature changes.

Stage 2 (stage of couperosis, i.e., of permanent erythema withtelangiectasia): certain patients also have oedema on the cheeks and theforehead.

Stage 3 (inflammatory stage, papulopustular rosacea): patients exhibitappearance of inflammatory papules and pustules, but without affectingthe sebaceous follicles, and thus, does not include cysts and comedones.

Stage 4 (rhinophyma stage): this late phase essentially affects men. Thepatients have a bumpy, voluminous red nose with sebaceous hyperplasiaand fibrous reordering of the connective tissue.

Typical treatment of rosacea includes oral or topical administration ofantibiotics such as tetracyclines, salicylic acid, anti-fungal agents,steroids, metronidazole (an anti-bacterial agent) and isotretinoin, ortreatment with anti-infectious agents such as azelaic acid.

The skin of patients suffering from signs and symptoms of rosacea isgenerally dry and sensitive, and requires the use of emollients (likesilicon oil, and fatty alcohols) and humectants (like glycerin orpropylene glycol) as a component of the vehicle used to deliver theappropriate drug during treatment of said signs and symptoms. Mostemollients are water insoluble oils and the use of surfactants is neededin order to emulsify them in the vehicle. In general, creams containboth emulsified emollients and humectants while gels usually containonly emollients. Therefore, in a preferred formulation, it may bebeneficial to include emollients and humectants in a cream to treat dryrosacea skin.

Papulopustular pathogens, such as bacteria and/or mites, are present onthe surface of the skin and in its upper layers. Therefore, in thetreatment of papulopustular rosacea, the vehicle needs to be designed tokeep a higher percentage of the active ingredient at the upper layers ofthe skin and reduce the amount of API into the deeper layers of theskin.

SUMMARY

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea, the regimen comprising topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1.0% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, wherein said pharmaceutical composition is acream or an emulsion.

Another exemplary embodiment of this application is a pharmaceuticalcomposition for use as a medicament in the treatment of rosacea, saidpharmaceutical composition comprising from about 1.0% w/w to about 10%w/w benzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is a cream or an emulsion.

Another exemplary embodiment of this application is the use of apharmaceutical composition for providing therapeutic treatment ofrosacea, said pharmaceutical composition comprising from about 1% w/w toabout 10% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is a cream or anemulsion.

In another exemplary embodiment, the total amount of benzoic acid in theskin of the subject after treatment with the pharmaceutical compositionis less than 11,000 ng. In certain embodiments, the total amount ofbenzoic acid in the skin of the subject after treatment with saidpharmaceutical composition ranges from about 4,000 ng to about 6,000 ng,more preferably ranges from about 4,500 ng to about 5,500 ng.

In another exemplary embodiment, the amount of benzoic acid in thestratum corneum and the epidermis of the skin of the subject aftertreatment with said pharmaceutical composition is higher than the amountof benzoic acid in the dermis of the skin of the subject after treatmentwith said pharmaceutical composition.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w of benzoyl peroxide.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 5% w/w of benzoyl peroxide.

In other exemplary embodiments, the benzoyl peroxide is selected from asolid, solution or suspension form.

In other exemplary embodiments, the rosacea is any oferythematotelengietatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.

In other exemplary embodiments, said pharmaceutical composition is anextended release formulation.

In other exemplary embodiments, the extended-release effect is obtainedby encapsulation, microencapsulation, microspheres or coating.

In other exemplary embodiments, the benzoyl peroxide is encapsulated ormicroencapsulated.

In other exemplary embodiments, the benzoyl peroxide is included in amicrosphere or a coating.

In other exemplary embodiments, irritation observed on the skin of thesubject after treatment with said pharmaceutical composition remainsconstant over time.

Details of other exemplary embodiments of the present disclosure will beincluded in the following detailed description and the accompanyingfigures. It is appreciated that certain features of the exemplaryembodiments described in this application, which are, for clarity,described in the context of separate embodiments, can also be providedin combination in a single embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the disclosure and to see how it can be carriedout in practice, embodiments will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIG. 1 is a graphical representation of mean cumulative amount ofbenzoic acid (ng), the conversion product of BPO, recovered fromepidermis and dermis 24 h post-application of 4 formulations, in each ofthe stratum corneum, epidermis and dermis layers of the skin.

FIG. 2 is a graphical representation of the total amount (ng) of thebenzoic acid that permeates the various layers of the skin.

FIG. 3 is a photograph of the irritation observed on the skin aftertreatment with various BPO formulations.

DETAILED DESCRIPTION

Multiple studies have been directed to the treatment of rosacea using apharmaceutical or dermatological active agent such as metronidazole,azelaic acid, sulfacetamide, brimonidine, ivermectin, permethrin andclindamycin, and with doxycycline, which is identified as the onlyFDA-approved treatment for rosacea (Oge et al., “Rosacea: Diagnosis andTreatment,” American Family Physician, v. 92(3), pp. 187-198 (2015); Gulet al., “A case of granulomatous rosacea successfully treated withpimecrolimus cream,” J. Derm. Treatment, 19, 313-315 (2008)).

Benzoyl peroxide (BPO) is generally identified as an anti-acne agent,used alone (U.S. Pat. No. 9,439,857; Wester et al., “Controlled releaseof benzoyl peroxide from a porous microsphere polymeric system canreduce topical irritancy,” J. Am. Acad. Derma. 24, 720-726 (1991);Sawleshwarkar, “Multicenter study to evaluate efficacy and irritationpotential of benzoyl peroxide 4% cream in hydrophase base (Brevoxyl) inacne vulgaris,” Ind. J. Derm. Vener. Lepro., 69(1), 19-22 (2003)) or incombination with a primary active such as avermectin (U.S.2011/0052515).

One such study includes a therapeutic regimen involving treatment ofacne rosacea in a group of patients in need of such treatment with 5%BPO-acetone gel for four weeks, followed by treatment of the same groupof patients with 10% BPO-acetone gel for an additional four weeks.(Montes et al., “Topical Treatment of Acne Rosacea with Benzoyl PeroxideAcetone Gel,” Therapeutics for the Clinician: New Reports on TreatmentModalities of Possible Interest to Patient-Caring Physicians, 32,185-190 (1983)). The Montes study showed a significantly better responseduring the five to eight weeks of treatment with 10% BPO-acetone gelcompared to the first four weeks of treatment with 5% BPO-acetone gel.Moreover, although Montes 1983 claims success in the treatment ofrosacea using a BPO-acetone gel, 25% of the patients in the study showedno improvement and 40% of the patients developed an irritation.Additionally, this study required increasing the amount of BPOadministered to the patients from 5% to 10% after week four. The resultsof the Montes 1983 study make it clear that BPO would not be suitablefor regular use in the treatment of rosacea, especially as a first linetreatment of rosacea.

Other studies show that, when used in the treatment of rosacea, BPO isgenerally combined with a primary active agent such as clindamycin(Breneman et al., “Double-blind, randomized, vehicle-controlled clinicaltrial of once-daily benzoyl peroxide/clindamycin topical gel in thetreatment of patients with severe rosacea,” Int. J. Derm., 43, 381-387(2004); Gold et al., “Use of Benzoyl Peroxide/Clindamycin gel in theonce daily treatment of moderate rosacea,” J. Amer. Acad. Dermat.,52(3), sup., P25 (2004); Leyden et al., “Blind photographic review for adouble blind, multicenter, placebo-controlled study comparing BenzoylPeroxide/Clindamycin and placebo for the treatment of rosacea,” J Amer.Acad. Dermat., 52(3), sup., P14 (2004); Goldgar et al., “TreatmentOptions for Acne Rosacea,” J Amer. Fam. Physician, 80(5), 461-468(2009)).

BPO is generally identified as only a possible second-line treatment ofrosacea following the use of another, different active. (Oge 2015, Table5; Goldgar 2009, “Key Recommendations for Practice”). When BPO was usedas the sole active agent for the treatment of rosacea, lesions werefound to be unresponsive. (Gul 2008).

These previous rosacea treatments with BPO alone or in combination withother agents, have been shown to have several drawbacks such asirritation and intolerance phenomena, especially when they areadministered for a prolonged period. (Crawford et al., “Rosacea: I.Etiology, pathogenesis, and subtype classification,” J. Am. Acad.Dermatol., 51, 327-341 (2004)). These treatments are only suppressiveand not curative, acting especially on the pustulous spasms occurringduring the inflammatory stage.

Such drawbacks associated with the treatment of rosacea involving theuse of BPO result in exclusion of BPO from standard rosacea treatmentmethods. For example, “A Review of the Current Modalities for theTreatment of Papulopustular Rosacea” identifies metronidazole,ivermectin and azelaic acid as topical therapies that were proveneffective for the treatment of rosacea. (McGregor et al., “A Review ofthe Current Modalities of the Treatment of Papulopustular Rosacea,”Dermatol. Clin. (2017)). While McGregor 2017 mentions alternatetherapies, such as sodium sulfacetanide/sulfur cream, clindamycin,tretinoin, calcineurin inhibitors and oral tretinoin, that may have someeffectiveness in the treatment of rosacea, notably, McGregor 2017 doesnot include, or even mention, BPO in the long list of possible treatmenttherapies described therein. The absence of BPO as a known treatment forrosacea is also evident in other studies. (Feaster et al., “Clinicaleffectiveness of novel rosacea therapies,” Current Op. Pharmacol., 46,14-18 (2019); Del Rosso et al., “Update on the Management of Rosaceafrom the American Acne & Rosacea Society (AARS); J. Clinical & AestheticDermat., 12 (6), 17-24 (2019)). The absence of BPO as a recognizedfirst-line treatment for rosacea is especially evident in Del Rosso,which is a well-known and respected authority on the treatment ofrosacea. The AARS review lists the Society's recommendation for rosaceatreatment, including topical metronidazole, topical azelaic acid, oraltetracyclines, ivermectin, topical alpha agonists, and oralisotretinoin, as well as “alternative therapies,” such assulfacetamide/sulfur, calcineurin inhibitors, retinoids, and permethrin.(See e.g., Table 1 of the AARS review.) BPO is not mentioned in the AARSreview either as a leading, or even an alternative, therapeutic agentfor the treatment of rosacea.

Considering the chronic nature of rosacea, there is a need for long-termtreatment of the disease, its symptoms and associated conditions, in asafe and effective manner. Thus, there exists a need for compositionsthat have long-term, and improved, efficacy in the treatment of rosacea,that impart greater tolerance to the active principles and that reduce,substantially minimize or do not have the side effects described in theprior art. There also exists a need for long-term, prolonged treatmentof rosacea without any accompanying adverse effects.

Benzoyl peroxide is highly unstable on the skin and decomposes rapidlyto its only metabolite, benzoic acid. Therefore, levels of benzoic acidin the skin layers are good indicator to presence of benzoyl peroxide inthese layers.

Additionally, as discussed above, in the treatment of papulopustularrosacea, the vehicle needs to be designed to keep a higher percentage ofthe active ingredient available at and/or within the upper layers of theskin and reduce the amount of API delivered to, absorbed in, and/orpenetrated into the deeper layers of the skin or penetrate the skin. Theeffect of surfactants on the enhancement of drug permeation through skinhas been well reviewed. Research in this area has proved the usefulnessof surfactants, such as chemical penetration enhancers in transdermaldrug delivery. In many instances, surfactants have been found to be moreeffective than other enhancers. (Som et al., “Status of surfactants aspenetration enhancers in transdermal drug delivery,” J Pharm BioalliedSci., 4(1), 2-9 (2012).) Nonionic surfactants, which are a safe class ofenhancers, offer a means of enhancing drug permeation through the skin.For example, Nokhodchi et. al. (“The enhancement effect of surfactantson the penetration of lorazepam through rat skin.,” Int J Pharm., 250,359-69 (2003)) reported two possible mechanisms by which the rate oftransport is enhanced using nonionic surfactants—first, the surfactantmay penetrate into the intercellular regions of the stratum corneum,increase fluidity and eventually solubilize and extract lipidcomponents; and second, penetration of surfactant into the intercellularmatrix followed by interaction and binding with keratin filaments mayresult in a disruption within the corneocyte. Furthermore, non-ionicsurfactants are able to emulsify sebum, thereby enhancing thethermodynamic coefficient of drugs and allowing it to penetrate into thecells more effectively (Smith et al. Percutaneous penetration enhancer.2nd ed. Boca Raton: Taylor and Francis (2005).)

Studies of the effect of carrier/vehicle on skin penetration have alsobeen carried out. Occlusive and lipophilic vehicles such as paraffin,fats and oils reduce water loss, increase the moisture content in theskin and thus promote drug penetration. (Flate et al., “In vitro skinmodels as a tool in optimization of drug formulation,” European Journalof Pharmaceutical Sciences, 75, 10-24 (2015); Stahl et al., “The effectof formulation vehicles on the in vitro percutaneous permeation ofibuprofen,” BMC Pharmacology, 11(12), 1-5 (2011).)

The effect of different 5% ibuprofen containing formulations (Ibutop®cream, Ibutop® gel, and ibuprofen solution in phosphate buffered saline)on the in vitro-percutaneous permeation of ibuprofen through skinemphasized the importance of the formulation on percutaneous permeationand skin reservoir has also been studied (Stahl 2011). Althoughibuprofen permeation out of the gel increases rapidly within the firstfour hours, the cream produced the highest ibuprofen delivery throughthe skin within 28 hours, followed by the solution and the gel.

BPO cream contains, nonionic surfactants, cyclomethicone, cetyl alcoholand glycerin. BPO gel is surfactants and oil free and contains onlyglycerin. Based on previous studies, BPO cream should have higher skinpenetration, similar to the findings on ibuprofen. Surprisingly, it wasfound in an ex vivo skin penetration study on human skin that bothencapsulated and non-encapsulated BPO creams have lower skin penetrationthan encapsulated and non-encapsulated BPO gels.

Advantages and features of the present disclosure, and methods foraccomplishing the same will be more clearly understood from exemplaryembodiments described below with reference to any accompanying figures.However, the present disclosure is not limited to the followingexemplary embodiments and can be implemented in various different forms.The exemplary embodiments are provided only to provide sufficientdisclosure of the present discoveries and to fully provide a personhaving ordinary skill in the art to which the present disclosurepertains within the technical field, and the present disclosure will bedefined by any appended claims and combinations thereof.

As used herein, like reference numerals generally denote like elementsthroughout the present specification. Further, in the followingdescription, a detailed explanation of well-known related technologiescan be omitted to avoid unnecessarily obscuring the subject matter ofthe present disclosure.

As used herein, terms such as “including” and “having” are generallyintended to allow other components to be included unless the terms areused in conjunction with the term “only.”

As used herein, the term “topical use” is meant to encompass the topicaladministration of an exemplary composition by formulating saidcomposition in any way known in the art, or in formulations disclosedherein, which are compatible with the skin, mucous membranes and/or theinteguments.

As used herein, the term “treating” or “treatment” includes curing acondition, treating a condition, preventing or substantially preventinga condition, treating symptoms of a condition, curing symptoms of acondition, ameliorating, reducing and/or minimizing symptoms of acondition, treating effects of a condition, ameliorating, reducingand/or minimizing effects of a condition, and preventing and/orsubstantially preventing results of a condition,

As used herein, the term “first-line therapy” or “first-line treatment”means a therapy or treatment for which its label does not include arequirement or recommendation that said therapy or treatment should beused only after other therapies or treatments were shown to beunsatisfactory or unsuccessful. It can also include a therapy and/ortreatment wherein no other actives (beyond the main active) areadministered to the individual subject in need.

As used herein, the term “success rate” corresponds to of the sum of thenumber of subjects achieving “clear” or “almost clear” skin on theinvestor global assessment (IGA) scale after treatment with thepharmaceutical composition, which can also be represented as apercentage of study subjects.

As used herein, the term “early onset” or “early onset of action” meansachieving a desired result and/or effect at a point in time that isearlier or even much early than achieved using a vehicle or other,conventional treatment approach. For example, it can mean achieving adesired result and/or effect no later than about 8 weeks from initialtreatment, preferably no later than about 4 weeks from initialtreatment, and more preferably no later than about 2 weeks from initialtreatment.

As used herein, the term “pharmaceutical composition” refers to acomposition comprising one or more active ingredients with othercomponents such as, for example, pharmaceutically acceptable ingredientsand/or excipients. The purpose of a pharmaceutical composition is tofacilitate administration of an active ingredient to a subject.

As used herein, the terms “pharmaceutically active agent” or “activeagent” or “active pharmaceutical ingredient” are interchangeable andmean the ingredient is a pharmaceutical drug, which is biologically-and/or chemically-active and is regulatory-approved or approvable assuch.

As used herein, the term “ingredient” refers to a pharmaceuticallyacceptable ingredient, which is included or is amenable to be includedin The FDA's Inactive Ingredient (IIG) database. Inactive ingredientscan sometimes exhibit some therapeutic effects, although they are notdrugs.

As used herein, the term “adverse events values” refers to an averagepercentage of subjects that experience any adverse events associatedwith the treatment of rosacea with a composition described and/orclaimed herein (usually on a surface of the skin of a subject treatedwith a composition described and/or claimed herein). A non-limiting listof such adverse events includes: irritation, dryness, scaling, itchingpurities, burning, stinging, combinations thereof and the like.

As used herein, the term “long-term” indicates prolonged use of apharmaceutical ingredient for at least about 12 weeks or longer, atleast about 40 weeks or longer, and more preferably at least about 52weeks or longer, in a treatment regimen.

As used herein, the term “inflammatory lesion” refers to papules andpustules present on the skin of a patient, and does not include nodulesand cysts.

As used herein, the term “papule” refers to a solid, elevatedinflammatory lesion equal to or less than about 5 mm in diameter.

As used herein, the term “pustule” refers to an elevated inflammatory,pus-containing lesion equal to or less than about 5 mm in diameter.

As used herein, the term “nodule” and/or “cyst” refers to palpable solidinflammatory lesion, greater than about 5 mm in diameter. The noduleand/or cyst may have depth but does not necessarily include elevation.

As used herein, the term “high skin penetration” and/or “intradermalpenetration” refers to a higher amount of the active ingredientdelivered to, absorbed in and/or penetrated into the upper skin layers(e.g., stratum corneum and epidermis) compared to the amount of theactive ingredient delivered to, absorbed in and/or penetrated into thedeeper layers (e.g., dermis) of the skin or thorough the skin into theblood or receptor solution.

Whenever a numerical range is indicated herewith, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicated number and asecond indicated number and “ranging/ranges from” a first indicatednumber “to” a second indicated number are used herein interchangeableand are meant to include the first and second indicated numbers and allfractional and integral numerals therebetween.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “10 μm” is intended to mean“about 10 μm.”

As used herein, numbers and/or numerical ranges preceded by the term“about” should not be considered to be limited to the recited range.Rather, numbers and/or numerical ranges preceded by the term “about”should be understood to include a range accepted by those skilled in theart for any given element in formations according to the subjectinvention.

As used herein, when a numerical value is preceded by the term “about,”the term “about” is intended to indicate +/−10%.

As used herein, the singular form “a,” “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” can include a pluralityof compounds, including combinations and/or mixtures thereof.

As used herein, the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, technical and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

It is appreciated that certain features of the exemplary embodimentsdescribed herein, which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a singleembodiment. Conversely, various features of the exemplary embodiments,which are, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitable sub-combination or assuitable in any other described embodiment. Certain features describedin the context of various embodiments are not to be considered essentialfeatures of those embodiments, unless the embodiment is inoperativewithout those elements.

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea, the regimen comprising topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1% w/w to about 10% w/w, preferably about 2.5% w/w to about 10%w/w, and more preferably, about 5% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, wherein said pharmaceutical composition is acream or an emulsion.

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of rosacea, the regimen comprising topicallyapplying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 1% w/w to about 10% w/w, preferably about 2.5% w/w to about 10%w/w, and more preferably, about 5% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, wherein said pharmaceutical composition is acream or an emulsion and wherein a total amount of benzoic acid in theskin of the subject after treatment with said pharmaceutical compositionis less than 11,000 ng, preferably from about 4000 ng to about 6000 ng,from about 4250 ng to about 5750 ng, from about 4500 ng to about 5500ng, from about 4750 ng to about 5250 ng.

Another exemplary embodiment of this application is a pharmaceuticalcomposition for use as a medicament in the treatment of rosacea, saidpharmaceutical composition comprising from about 1% w/w to about 10%w/w, preferably about 2.5% w/w to about 10% w/w, and more preferably,about 5% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is a cream or anemulsion.

Another exemplary embodiment of this application is a pharmaceuticalcomposition for use as a medicament in the treatment of rosacea, saidpharmaceutical composition comprising from about 1% w/w to about 10%w/w, preferably about 2.5% w/w to about 10% w/w, and more preferably,about 5% w/w benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is a cream or anemulsion, and wherein a total amount of benzoic acid in the skin of thesubject after treatment with the pharmaceutical composition is less than11,000 ng, preferably from about 4000 ng to about 6000 ng, from about4250 ng to about 5750 ng, from about 4500 ng to about 5500 ng, fromabout 4750 ng to about 5250 ng.

Another exemplary embodiment of this application is the use of apharmaceutical composition for providing therapeutic treatment ofrosacea, said pharmaceutical composition comprising from about 1% w/w toabout 10% w/w, preferably about 2.5% w/w to about 10% w/w, and morepreferably, 5.0% w/w/benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is a cream or anemulsion.

Another exemplary embodiment of this application is the use of apharmaceutical composition for providing therapeutic treatment ofrosacea, said pharmaceutical composition comprising from about 1% w/w toabout 10% w/w, preferably about 2.5% w/w to about 10% w/w, and morepreferably, 5.0% w/w/benzoyl peroxide as an active ingredient, and apharmaceutically acceptable carrier or excipient, wherein the benzoylperoxide is the only active ingredient in said pharmaceuticalcomposition, wherein said pharmaceutical composition is a cream or anemulsion, and wherein a total amount of benzoic acid in the skin of thesubject after treatment with the pharmaceutical composition is less than11,000 ng, preferably from about 4000 ng to about 6000 ng, from about4250 ng to about 5750 ng, from about 4500 ng to about 5500 ng, fromabout 4750 ng to about 5250 ng.

In another exemplary embodiment, the amount of benzoic acid in thestratum corneum and the epidermis of the skin of the subject aftertreatment with said pharmaceutical composition is higher than the amountof benzoic acid in the dermis of the skin of the subject after treatmentwith said pharmaceutical composition.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the benzoyl peroxide is selected from asolid, solution or suspension form.

In other exemplary embodiments, the rosacea is any oferythematotelengietatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.

In other exemplary embodiments, said pharmaceutical composition is anextended release formulation.

In other exemplary embodiments, the extended-release effect is obtainedby encapsulation, microencapsulation, microspheres or coating.

In other exemplary embodiments, the benzoyl peroxide is encapsulated ormicroencapsulated.

In other exemplary embodiments, the benzoyl peroxide is included in amicrosphere or a coating.

In other exemplary embodiments, irritation observed on the skin of thesubject after treatment with said pharmaceutical composition remainsconstant over time.

In some further embodiments, the composition further comprises at leastone non pharmaceutical active additive selected from the groupconsisting of chelating agents, antioxidants, sunscreens, preservatives,fillers, electrolytes, humectants, dyes, mineral or organic acids orbases, fragrances, essential oils, moisturizers, vitamins, essentialfatty acids, sphingolipids, self-tanning compounds, calmatives andskin-protecting agents, pro-penetrating agents and gelling agents, or amixture and/or combination thereof.

In other embodiments, the composition is formulated into a topicallyapplicable, physiologically acceptable medium comprising of: (a) atleast one member selected from the group consisting of water, alcohols,oils, fatty substances and waxes; and (b) at least one additive selectedfrom the group consisting of chelating agents, antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants, dyes, mineral acids,mineral bases, organic acids, organic bases, fragrances, essential oils,moisturizers, vitamins, essential fatty acids, sphingolipids,self-tanning compounds, calmatives, skin-protecting agents,pro-penetrating agents, gelling agents, emulsifiers, co-emulsifiers, andmixtures and/or combinations thereof.

In some embodiments the composition is formulated as an emulsion(including an oil-in-water emulsion, a water-in-oil emulsion, multipleemulsions and microemulsions). In other embodiments, the composition isformulated as a cream.

The compositions described in exemplary embodiments herein arepharmaceutical compositions, and especially dermatological compositions,which can be in any galenical form conventionally used for topicalapplication. By addition of a fatty or oily phase, they can also be inthe form of dispersions of the lotion or serum type, emulsions of liquidor semi-liquid consistency of the milk type obtained by dispersing afatty phase in an aqueous phase (O/W) or conversely (W/O), orsuspensions or emulsions of soft, semiliquid or solid consistency of thecream, gel or ointment type, or alternatively multiple emulsions (W/O/Wor O/W/O), microemulsions, microcapsules, microparticles and/orvesicular dispersions of ionic and/or nonionic type, and/or wax/aqueousphase dispersions. These compositions are formulated according to theusual methods.

In further embodiments, the composition comprises, as a singlepharmaceutical active agent, benzoyl peroxide in a solid form, fortopical use in the treatment of rosacea, in an oil in water emulsioncomprising a polyoxylstearate and a glycerylstearate. Various methodsfor the preparation of the BPO-containing compositions are described inU.S. Application Publication Nos. 2010/0016443, 2017/0281571 and2018/0147165 and U.S. Pat. No. 9,687,465.

In some embodiments, the ratio of said polyoxylstearate to saidglycerylstearate is in the range of about 0.1:10 to about 10:0.1.

In yet further embodiments, said polyoxylstearate is selected from thegroup consisting of Polyoxyl-8 stearate, Polyoxyl-20 stearate,Polyoxyl-40 stearate, Polyoxyl-100 stearate and combinations and/ormixtures thereof.

In further embodiments, said glycerylstearate is selected from the groupconsisting of glyceryl mono-stearate, glyceryl di-stearate andcombinations and/or mixtures thereof.

In other embodiments, said polyoxylstearate in said composition is inthe range of from about 0.1% w/w to about 30% w/w.

In further embodiments, the amount of said glycerylstearate in saidcomposition is in the range of from about 0.1% w/w to about 30% w/w.

In other embodiments, said composition further comprises at least onefatty alcohol.

In other embodiments, said at least one fatty alcohol is selected fromthe group consisting of octyl alcohol, 2-ethyl hexanol. nonyl alcohol,decyl alcohol, undecanol, dodecyl alcohol, tridecyl alcohol, tetradecylalcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol,heptadecyl alcohol, cetostearyl alcohol, stearyl alcohol, isostearylalcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,elaidolinolenyl alcohol, ricinoleyl alcohol, nonadecyl alcohol,arachidyl alcohol, heneicosyl alcohol. behenyl alcohol, erucyl alcohol,lignoceryl alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol,myricyl alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol andcombinations and/or mixtures thereof.

In further embodiments, the amount of said at least one fatty alcohol insaid composition is in the range of from about 0.2% w/w to about 50%w/w.

In yet other embodiments, said composition further comprises apolyacrylic acid homopolymer or copolymer.

In other embodiments, said oil in said oil in water emulsion is selectedfrom the group consisting of paraffin oil, isopropyl myristate,caprylic/capric triglyceride, squalane, squalene, almond oil, castoroil, olive oil, jojoba oil, sunflower oil, soybean oil, grape seed oil,dimethicone, cyclomethicone and combinations and/or mixtures thereof.

In further embodiments, said oil in present in the composition in anamount in the range of from about 0.05% w/w to about 50% w/w.

In some embodiments, said water in said oil in water emulsion furthercomprises at least one water soluble humectant.

In other embodiments, said at least one water soluble humectant isselected from the group consisting of propylene glycol, glycerin,polyethylene glycol-X and combinations and/or mixtures thereof, where Xis in the range of from about 200 to about 10,000.

In some embodiments, the composition comprises said solid BPO in acontrolled and/or slowed release drug delivery system. In furtherembodiments, said controlled and/or slowed release drug delivery systemis an encapsulation in a microcapsule, wherein said solid BPO isembedded in said microcapsule. When referring to a “controlled and/orslowed release drug delivery system” it should be understood to relateto a delivery system (which in the present application is a topicaldelivery system) that enables the release of the pharmaceutical activeagent in predetermined amounts over a specified period. In someembodiments, said system is a core-shell system of a microcapsule and/ora porous matrix structure, such as, for example, a microsponge. The term“embedded” should be understood to encompass an inert system thatprovides a barrier between the pharmaceutical active agent, i.e. BPO,and its surrounding environment in the composition. In some embodiments,said agent is entrapped and/or encapsulated in said controlled releasesystem.

In some embodiments, said core of said microcapsule comprises orconsists of said solid BPO.

In some further embodiments, said microcapsules are a core shellmicrocapsule. The shell comprises at least one inorganic polymer. Insome other embodiments, said inorganic polymer of said shell is a metaloxide or semi-metal oxide shell (layer).

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising orconsisting of solid BPO.

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising solidBPO is prepared by a process comprising the steps of:

(a) contacting a solid BPO particulate matter with an ionic additive andan aqueous medium to obtain a dispersion of said particulate matterhaving positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide layer thereon thereby to obtain particulatematter coated by a metal oxide coating layer;

(c) repeating step (b) at least 4 more times: and

(d) aging said coating layer.

As used herein, the term “solid BPO particulate matter” refers to asolid BPO having solubility in water of less than about 1% w/w,typically less than about 0.5% and at times less than about 0.1% w/w atroom temperature (about 20° C.). The “solid BPO particulate matter”constitutes the “core” of the particles obtained by the process. Thesolid BPO particulate matter, is, in some embodiments, in such a stateof subdivision that it can be suspended in water, e.g., in the form of afinely-divided powder having a D₉₀ (see definition below), in someembodiments in the range of from about 0.3 to about 50 microns. Such aparticulate matter can be readily suspended in an aqueous systems bystirring, with or without the aid of a surfactant.

The terms “solid BPO particulate matter” and “particulate matter” willbe used interchangeably.

In the present application, the terms “layer”, “coating” or “shell” andsimilar terms, refer to a layer of metal oxide or semi-metal oxideformed around a particle or particulate matter. The layer or coatingneed not always be complete or uniform and need not necessarily lead tocomplete coverage of the particulate matter or particle surface. It isappreciated that upon repetition of the coating steps as the coatingprocess proceeds a more uniform coating and more complete coverage ofthe particulate matter is obtained.

The term “dispersion,” as used herein, in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.Step (a) of the process can further comprise reducing the particle sizeof the particulate matter to the desired particle size, for example, bymilling or homogenization.

The core (i.e., solid, BPO particulate matter) can be of any shape, forexample, rod-like, plate-like, ellipsoidal, cubic, spherical shape,combinations thereof and the like.

Reference to the size of particles will be made through their D₉₀, whichmeans that about 90% of the particles have the stated dimension or less(measured by volume). Thus, for example, for spherical particles statedto have a diameter of about 10 micrometer (“microns”), this means thatthe particles have a D₉₀ of about 10 microns. The D₉₀ can be measured bylaser diffraction. For particles having a shape other than spheres, theD₉₀ refers to the mean average of the diameter of a plurality ofparticles.

In the case of cores having a spherical shape, the D₉₀ can be in therange of from about 0.3 to 90 microns, in some embodiments from about0.3 to about 50 microns, in some other embodiments from about 1 to about50 microns, in some further embodiments from about 5 to about 30microns. As used herein, the phrase “D₉₀ can be in the range of fromabout 0.3 microns to about 90 microns” means about 90% by volume of theparticles (in this case the particle's core) can be less than or equalto a value in the range of from about 0.3 microns to about 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side can be in the range of from about 0.3to about 80 microns, in some embodiments from about 0.3 to about 40microns, in some further embodiments from about 0.8 to about 40 microns,in some further embodiments from about 4 to about 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the rangeof from about 10 to about 100 microns, in some embodiments from about 15to about 50 microns; and the smallest dimension is typically in therange of from about 0.5 to about 20 microns, in some further embodimentsfrom about 2 to about 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide or semi-metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process canat times be formed from two or more original particles of the solid BPOparticulate and can accordingly include at times more than one core,such cores being separated from each other by a metal oxide region.

The weight of the solid BPO particulate (core material) based on thetotal weight of the particle can be in the range of from about 99% w/wto about 50% w/w, in some embodiments in the range of from about 97% w/wto about 50% w/w. The core material can be in a crystalline form,amorphous form, or combination thereof. The core material can be acosmetic, pharmaceutical or an agrochemical active ingredient.

EXEMPLARY EMBODIMENTS

BPO-containing compositions were prepared following the variouspreparation methods described in U.S. Application Publication Nos.2010/0016443, 2017/0281571 and 2018/0147165 and U.S. Pat. No. 9,687,465,the contents of which are incorporated herein, by reference, in theirentirety.

Description: The aim of this study was to perform in vitro permeationand penetration testing on BPO-containing formulations used to treatrosacea. The study objectives were achieved via implementation of anHPLC analytical method and a pilot in vitro skin permeation andpenetration experiments using four different BPO-containingformulations, which are described in Tables 1 to 4 below:

TABLE 1 Components of Formulation #1 (5% E-BPO Gel) % w/w E-BPO 15%Suspension 33.33 Carbopol 980 1.2 Tromethamine 30% Solution pHadjustment EDTA Disodium Salt 0.1 Glycerin 99.5% 5.0 Phenoxyethanol 0.1Purified water or higher grade Up to 100

TABLE 2 Components of Formulation #2 (5% BPO Gel) % w/w BPO 75% 6.7Placebo for E-BPO 15% Suspension 27.78 Carbopol 980 1.2 Tromethamine 30%Solution pH adjustment EDTA Disodium Salt 0.1 Glycerin 99.5% 5.0Phenoxyethanol 0.1 Purified water or higher grade Up to 100

TABLE 3 Components of Formulation #3 (5% E-BPO Cream) % w/w E-BPO, 15%Suspension 33.33 Polyoxyl 100 stearate 2.0 Cetyl alcohol 3.0Cyclomethicone 5-NF 4.0 Glyceryl Mono- and Di-stearate 3.0 HydrochloricAcid 10% pH adjustment Citric Acid, anhydrous 0.4 Sodium HydroxidePellets pH adjustment EDTA Disodium Salt 0.1 Glycerin 99.5% 4.0Phenoxymethanol 0.5 Purified water or higher grade Up to 100

TABLE 4 Components of Formulation #4 (5% BPO Cream) % w/w BPO 75% 6.7Placebo for E-BPO 15% Suspension 27.8 Polyoxyl 100 stearate 2.0 Cetylalcohol 3.0 Cyclomethicone 5-NF 4.0 Glyceryl Mono- and Di-stearate 3.0Hydrochloric Acid 10% pH adjustment Citric Acid, anhydrous 0.4 SodiumHydroxide Pellets pH adjustment EDTA Disodium Salt 0.1 Glycerin 99.5%4.0 Phenoxymethanol 0.5 Purified water or higher grade Up to 100

Pilot IVPT Study Design:

Human skin, freshly excised from one skin donor was mounted between thedonor and receptor compartment of the diffusion cell (with an exposeddosing surface area of ˜0.6 cm² for each replicate). The skin was dosedwith ca. 12 μL of each of Formulations 1 to 4 to achieve a dose of ˜20μL/cm². Skin was also mounted in a blank cell to which no formulationwas applied. A receptor solution stir rate of 600 rpm was employed, and0.2 mL of receptor solution was sampled at approximately about 1 hour,about 2 hours, about 4 hours, about 6 hours, about 8 hours and about 24hours. Receptor solution was analyzed using a single HPLC analyticalmethod for both benzoyl peroxide and conversion product, benzoic acid.

After about 24 hours, the residual formulation was removed from thesurface of the skin and the skin surface was tape stripped up to 5 timesto remove residual formulation and the top of the skin surface layers(stratum corneum). The epidermis was then heat-separated from the dermisby placing the skin into an incubator at 60° C. for 2 min, followed bymanual separation. The amount of benzoyl peroxide, and its metabolitebenzoic acid, delivered to the stratum corneum, epidermis, and dermiswas then determined by HPLC.

Penetration and Permeation Results:

The mean amounts of benzoic acid (BA) (ng) recovered from the stratumcorneum, epidermis and dermis after 24 h following application of thefour formulations described above are shown in Table 5 and FIG. 1 ,while the total amount of benzoic acid (ng) recovered from the skin foreach formulation is shown in Table 6 and FIG. 2 . Samples below thelimit of quantitation were set to a value of the limit of quantitation(100 ng).

TABLE 5 Amount of BA in the Amount of BA in the Amount of BA in theStratum corneum (ng) Epidermis (ng) Dermis (ng) Std. Std. Std. Std. Std.Std. Formulation N Mean Dev. Error N Mean Dev. Error N Mean Dev. Error#1 5 348 74 33 5 5472 3805 1702 5 5771 1768 791 #2 5 393 79 35 4 9991560 280 5 2762 678 303 #3 5 300 0 0 4 2464 280 140 5 1798 131 59 #4 4300 0 0 4 2712 246 123 5 2479 1516 678

TABLE 6 Total amount of BA in the skin (ng) Formulation #1 11591Formulation #2 13146 Formulation #3 4562 Formulation #4 5491

Additionally, the mean cumulative amount of benzoic acid (ng/cm²)recovered from the receptor solution (RC), stratum corneum (SC),epidermis, and dermis at 24 h post-application of the four formulationsis shown in FIG. 3 . Bars represent the cumulative amount of benzoylperoxide and benzoic acid from five replicates and one donor (n=4-5).Error bars represent standard error of the mean.

Skin Irritation Tests:

Enhancing penetration of BPO into the deep layers of the skin may causeskin irritation. Two different mixtures of BPO cream with a penetrationenhancer transcutol, and humectant IPM were prepared by combining 5%E-BPO in a 120 ml polypropylene until a homogenous mixture was obtained.A third sample with water (without a penetrating agent) was used as areference. The three mixtures have the following compositions:

Mixture #1: 45 g 5% E-BPO cream with 5 g water;

Mixture #2: 45 g 5% E-BPO cream with 5 g Transcutol (penetrationenhancer);

Mixture #3: 45 g 5% E-BPO cream with 5 g Isopropyl myristate.

The amount of sample mixture in each patch was about 0.11 g to about0.15 g, and all samples were prepared in duplicate. The samples wereapplied on the skin of a person and kept under occlusion for 6 hrs.After 6 hours the patch was removed and the skin was cleaned. Irritationwas developed 2 h after the removal of the patch and remained constantfor 48 h.

Irritation from the various samples was evaluated on a 0-3 scale asshown in Table 7 below. FIG. 3 is a photograph of the irritationobserved on the skin.

TABLE 7 Mixture #1 Mixture #2 Mixture #3 FIG. 3 (sample) 0.5 2.0 0.0FIG. 3 (duplicate) 0.0 2.0 0.5

The results show that transcutol as a skin penetrating agent causedmoderate skin irritation. The skin irritation coming from the referenceand the sample with the IPM was negligible. It is clear that increasingskin penetration causes skin irritation, therefore the formulationsshould be designed to avoid penetration of BPO into the deep layers ofskin as shown in the present invention.

As shown by the results of Table 6 and FIG. 2 , E-BPO gel (Formulation#1) and BPO Gel (Formulation #2) have a high amount of skin penetrationand permeation compared to E-BPO Cream (Formulation #3) and BPO Cream(Formulation #4). However, as shown in Table 5 and FIG. 1 , asignificantly higher percentage of the active ingredient (BPO orencapsulated BPO) is available at the upper layers (stratum corneum andepidermis) of the skin for the cream compositions, which reduces theamount of API present in the deeper layers (dermis) of the skin. Asdiscussed above, this is a desired level of skin penetration for thetreatment of papulopustular rosacea. Additionally, any skin irritationobserved after treating with the BPO formulations remains constant afterabout 2 hours. Accordingly, the BPO cream and encapsulated BPO creamhave unexpectedly superior properties in the treatment of papulopustularrosacea.

Although the exemplary embodiments of the present disclosure have beendescribed in detail with reference to the accompanying examples anddrawings, the present disclosure is not limited thereto and can beembodied in many different forms without departing from the technicalconcept of the present disclosure. Therefore, the exemplary embodimentsof the present disclosure are provided for illustrative purposes onlyand are not intended to limit the technical concept of the presentdisclosure. The protective scope of the present disclosure should beconstrued based on any appended claims and combinations thereof, and allthe technical concepts in the equivalent scope thereof should beconstrued as falling within the scope of the present disclosure. Asvarious changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense. Other embodiments within thescope of the claims herein will be apparent to one skilled in the artfrom consideration of the specification or practice of the exemplaryembodiments disclosed herein. It is intended that the specification beconsidered exemplary only, with the scope and spirit of the describedsubject matter being indicated by the claims.

What is claimed is:
 1. A regimen for the therapeutic treatment ofrosacea, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 2.5% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein: the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition; the benzoylperoxide is not encapsulated within a microcapsule or microsphereconsisting of a metal oxide or a semi-metal oxide; and saidpharmaceutical composition comprises a fatty phase and/or an oily phasethat forms a barrier between the benzoyl peroxide and its surroundingenvironment in the composition.
 2. The regimen of claim 1, wherein saidpharmaceutical composition comprises about 2.5% w/w to about 5% w/w ofbenzoyl peroxide.
 3. The regimen of claim 1, wherein the benzoylperoxide is not encapsulated within a microcapsule.
 4. The regimen ofclaim 1, wherein after the topical application, skin irritation of thesubject, and the amount of benzoic acid in the dermis of the skin of thesubject, are decreased, compared to skin irritation of the subject andthe amount of benzoic acid in the dermis of the skin of the subject,respectively, after topical application of a correspondingpharmaceutical composition without the fatty phase and/or the oilyphase.
 5. The regimen of claim 1, wherein an amount of benzoic acid inthe stratum corneum and the epidermis of the skin of the subject aftertreatment with said pharmaceutical composition is higher than an amountof benzoic acid in the dermis of the skin of the subject after treatmentwith said pharmaceutical composition.
 6. The regimen of claim 1, whereinthe benzoyl peroxide is the sole active ingredient administered to thesubject during the duration of the regimen.
 7. The regimen of claim 1,wherein the pharmaceutical composition comprises about 5% w/w of benzoylperoxide.
 8. The regimen of claim 1, wherein the benzoyl peroxide isselected from a solid, solution or suspension form.
 9. The regimen ofclaim 1, wherein the rosacea is any of erythematotelangiectatic rosacea,papulopustular rosacea, phymatous rosacea or ocular rosacea.
 10. Theregimen of claim 1, wherein said pharmaceutical composition is anextended-release formulation.
 11. The regimen of claim 10, wherein theextended-release effect is obtained by encapsulation,microencapsulation, microspheres or coating.
 12. The regimen of claim 1,wherein irritation observed on the skin of the subject after treatmentwith said pharmaceutical composition remains constant over time.
 13. Theregimen of claim 10, wherein the extended-release effect is obtained bythe fatty phase and/or the oily phase that forms a barrier between thebenzoyl peroxide and its surrounding environment in the composition. 14.The regimen of claim 1, wherein the benzoyl peroxide is not encapsulatedwithin a microcapsule comprising an inorganic polymer.
 15. The regimenof claim 1, wherein the pharmaceutical composition does not comprise agelling agent.
 16. The regimen of claim 1, wherein: the fatty phaseand/or the oily phase is dispersed in an aqueous phase; or thepharmaceutical composition comprises an aqueous phase dispersed in thefatty phase and/or the oily phase.
 17. The regimen of claim 1, whereinsaid pharmaceutical composition is a cream.
 18. The regimen of claim 1,wherein the irritation is reduced when evaluated on a 0-3 scale.
 19. Aregimen for the therapeutic treatment of rosacea, the regimen comprisingtopically applying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 2.5% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is encapsulated within a microcapsule andis the only active ingredient in said pharmaceutical composition,wherein said pharmaceutical composition is a cream, and wherein anamount of benzoic acid in the stratum corneum and the epidermis of theskin of the subject after treatment with said pharmaceutical compositionis higher than an amount of benzoic acid in the dermis of the skin ofthe subject after treatment with said pharmaceutical composition. 20.The regimen of claim 19, wherein the amount of benzoic acid in thestratum corneum and the epidermis of the skin of the subject is higherthan the amount of benzoic acid in the dermis of the skin of the subjectwhen measured by high-performance liquid chromatography (HPLC).
 21. Theregimen of claim 19, wherein the amount of benzoic acid in the stratumcorneum and the epidermis of the skin of the subject is higher than theamount of benzoic acid in the dermis of the skin of the subject whenmeasured by HPLC about 24 hours following the application of thepharmaceutical composition to the skin of the subject.
 22. The regimenof claim 19, wherein the amount of benzoic acid in the stratum corneumand the epidermis of the skin of the subject is substantially higherthan the amount of benzoic acid in the dermis of the skin of the subjectafter treatment with said pharmaceutical composition.
 23. The regimen ofclaim 19, wherein irritation observed on the skin of the subject aftertreatment with said pharmaceutical composition is reduced compared toafter treatment with a corresponding pharmaceutical composition in whichthe benzoyl peroxide is not encapsulated within a microcapsule.
 24. Theregimen of claim 23, wherein the irritation is reduced when evaluated ona 0-3 scale.
 25. The regimen of claim 19, wherein the microcapsulecomprises an inorganic polymer.
 26. The regimen of claim 19, wherein thebenzoyl peroxide is the sole active ingredient administered to thesubject during the duration of the regimen.
 27. The regimen of claim 19,wherein the pharmaceutical composition comprises about 5% w/w of benzoylperoxide.
 28. The regimen of claim 19, wherein the benzoyl peroxide isselected from a solid, solution or suspension form.
 29. The regimen ofclaim 19, wherein the rosacea is any of erythematotelangiectaticrosacea, papulopustular rosacea, phymatous rosacea or ocular rosacea.30. The regimen of claim 19, wherein said pharmaceutical composition isan extended-release formulation.
 31. The regimen of claim 19, whereinthe pharmaceutical composition does not comprise a gelling agent. 32.The regimen of claim 19, wherein irritation observed on the skin of thesubject after treatment with said pharmaceutical composition remainsconstant over time.
 33. A regimen for the therapeutic treatment ofrosacea, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 2.5% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein atotal amount of benzoic acid in the skin of the subject after treatmentwith said pharmaceutical composition is less than about 18,333 ng/cm²,and wherein said pharmaceutical composition is a cream.
 34. The regimenof claim 33, wherein the amount of benzoic acid in the skin of thesubject after treatment with said pharmaceutical composition ranges fromabout 6,667 ng/cm² to about 10,000 ng/cm².
 35. The regimen of claim 33,wherein the amount of benzoic acid in the skin of the subject aftertreatment with said pharmaceutical composition ranges from about 7,500ng/cm² to about 9,167 ng/cm².
 36. The regimen of claim 33, wherein thebenzoyl peroxide is not encapsulated within a microcapsule or a coating.37. The regimen of claim 33, wherein the benzoyl peroxide isencapsulated within a microcapsule or a coating.
 38. The regimen ofclaim 37, wherein the benzoyl peroxide is encapsulated within amicrocapsule comprising an inorganic polymer.
 39. The regimen of claim33, wherein the benzoyl peroxide is the sole active ingredientadministered to the subject during the duration of the regimen.
 40. Theregimen of claim 33, wherein the pharmaceutical composition comprisesabout 5% w/w of benzoyl peroxide.
 41. The regimen of claim 33, whereinthe benzoyl peroxide is selected from a solid, solution or suspensionform.
 42. The regimen of claim 33, wherein the rosacea is any oferythematotelangiectatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.
 43. The regimen of claim 33, wherein saidpharmaceutical composition is an extended-release formulation.
 44. Theregimen of claim 33, wherein the pharmaceutical composition does notcomprise a gelling agent.
 45. The regimen of claim 33, whereinirritation observed on the skin of the subject after treatment with saidpharmaceutical composition remains constant over time.
 46. The regimenof claim 33, wherein irritation observed on the skin of the subjectafter treatment with said pharmaceutical composition is reduced comparedto after treatment with a corresponding pharmaceutical composition thatis not a cream.
 47. The regimen of claim 46, wherein the irritation isreduced when evaluated on a 0-3 scale.
 48. The regimen of claim 36,wherein irritation observed on the skin of the subject after treatmentwith said pharmaceutical composition is reduced compared to aftertreatment with a corresponding pharmaceutical composition that is not acream.
 49. The regimen of claim 48, wherein the irritation is reducedwhen evaluated on a 0-3 scale.
 50. The regimen of claim 37, whereinirritation observed on the skin of the subject after treatment with saidpharmaceutical composition is reduced compared to after treatment with acorresponding pharmaceutical composition that is not a cream.
 51. Theregimen of claim 50, wherein the irritation is reduced when evaluated ona 0-3 scale.
 52. The regimen of claim 1, wherein the benzoyl peroxide isnot encapsulated within a microcapsule or microsphere comprising a metaloxide or a semi-metal oxide.